This project is one of two linked (R21/R33) applications representing a collaborative effort in real-time fMRI between Omneuron (Dr. deCharms -1R21DA26098-01) and University of Pennsylvania School of Medicine (Dr. Childress). The overall goal of the linked project is to determine whether substance abuse patients can use real-time fMRI feedback technology to control distributed patterns of activity in their own motivational circuitry, with associated reductions in drug craving. The technology will be applied in two substance abuse populations: nicotine-dependent smokers (at Omneuron), and cocaine users (at Penn). The laboratories at Omneuron have made significant advances in the development and clinical application of real-time fMRI, demonstrating that participants can learn to control a target brain region involved in pain modulation, and that this training can produce long-lasting clinical benefits. Though control of a single brain region in addicted individuals, with behavioral effect (e.g., reduction in craving), is a very useful proof-of- concept step, both research teams recognize that the information derived from the distributed pattern of brain activity in the drug motivational circuit is likely to be even more effective than feedback from a single target region, as it reflects far more information about the target state. To explore this approach, the two teams in the R21 phase will (Aim 1) demonstrate the feasibility of measuring distributed patterns of brain activity during attempted inhibition of craving, developing "reference patterns" of brain activation associated with successful craving inhibition, and (Aim 2) demonstrate the feasibility of monitoring activity in this distributed pattern in real-time. For the R33 phase, both teams will test whether drug users can learn to mimic a distributed pattern of brain activation associated with craving inhibition (Aim 3), will measure resultant control over brain activation measured using rtfMRI (Aim 4), and will measure any associated decreases in craving and substance use (Aim 5), and will compare these effects with sham-rtfMRI- feedback controls. At Omneuron the subjects will be nicotine-dependent smokers, and at Penn the subjects will be treatment-seeking cocaine patients. These developmental projects are scientifically linked, taking advantage of the complementary strengths in real-time fMRI training technology at Omneuron and in the circuitry for drug motivation at Penn. These linked collaborative efforts will speed development of rtfMRI pattern training in addiction, enabling future clinical trials. PUBLIC HEALTH RELEVANCE: This project is one of two linked collaborative applications from the University of Pennsylvania and from Omneuron. This research program will test the use of real-time fMRI feedback of patterned brain activation for training subjects to decrease drug-related craving in two subject populations: nicotine-dependent smokers and treatment-seeking cocaine patients. This may provide a means to train patients to control substance abuse by controlling their brain activation.